engleski

Distribution of major gangliosides in brains of wild type mice and mice deficient for enzymes in ganglioside biosynthesis

Gangliosides, sialylated glycosphingolipids, are major glycans in the brain and the predominant glycans of nerve cells. All mammals express the same four major brain gangliosides, GM1, GD1a, GD1b, and GT1b, which vary in the number and linkage positions of sialic acids and together represent ~90% of the total brain ganglioside content. A key branch point in ganglioside biosynthesis is the conversion of GM3 to GD3 by the Siat8a gene product (CMP-NeuAc:GM3 2, 8-sialyltransferase), leading subsequently to GD1b and GT1b. Alternatively, GM3 is converted to GM2 by the Galgt1 gene product (UDP-GalNAc:GM3/GD3 N-acetylgalactosaminyltransferase), leading subsequently to GM1 and GD1a. Wild type, Siat8a-null and Galgt1-null mice have the same level of total brain gangliosides. Siat8a-null mice lack GD1b and GT1b and express correspondingly higher concentrations of GM1 and GD1a. Galgt1-null mice lack all of the major brain gangliosides, but express the corresponding concentrations of GM3 and GD3. Using highly specific monoclonal IgG antibodies we studied the distribution of GD3, GM1, GD1a, GD1b and GT1b gangliosides in brains of wild type mice, Siat8a-null mice, and Galgt1-null mice. In wild type mice, GM1 was expressed preferentially in myelinated pathways (white matter), GD1a in gray matter, and GD1b and GT1b in both, but at higher concentrations in gray matter. GD3 staining was essentially absent in adult wild type mice. In Galgt1-null mice GM1, GD1a, GD1b, and GT1b were absent. GD3, which is the major ganglioside in Galgt1-null brain, was found on neuronal and glial cells, but was lacking in myelinated pathways. In Siat8a-null mice, GD3, GD1b and GT1b were absent. As in wild type mice, GM1 staining in Siat8a-null mice was still predominantly in the white matter whereas GD1a staining was predominantly in the gray matter. However, the white/gray separation of GM1 and GD1a (respectively) was less abrupt in Siat8a-null mice than in wild type mice. We conclude that the total level of brain gangliosides is controlled early in the biosynthetic pathway, that different brain structures (gray matter/white matter) express different major brain gangliosides, and that the distribution of remaining ganglioside species in genetically altered mice generally reflects interruption of the underlying biosynthetic pathways specific for the brain structures in which they are expressed. Supported by Croatian ministry of science, grant number 0219021 and NIH NS37096.

gangliosides; Galgt1-null mice; Siat8a-null mice

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